Patofisiología de la placa coronaria aterosclerótica vulnerable y síndromes coronarios agudos / Pathophysiology Of The Vulnerable Atherosclerotic Coronary Plaque And Acute Coronary Syndromes

La ruptura de la placa aterosclerótica es responsable por dos tercios de los síndromes coronarios agudos (SCA) y por la muerte súbita cardiaca. El fibroateroma de capa fina (TCFA), se caracteriza por la presencia de un grande acumulo de lípidos recubiertos por una capa fibrosa fina que mide <65 µm, y es reconocido como el precursor de la ruptura de la placa. Las enfermedades cardiovasculares son responsables por 38% de todas las muertes en los Estados Unidos y constituyen la principal causa de muerte en hombres menores de 65 años en Europa. La cardiopatía isquémica (EAC) incluye los síndromes coronarios estables y crónicos (AE), los síndromes coronarios agudos (AI/IAM), insuficiencia cardiaca congestiva, muerte súbita de origen cardiovascular e isquemia silenciosa. Las características más obvias, que diferencian los pacientes con síndromes coronarios agudos (SCA) de los pacientes con EAC estable son: 1) estenosis coronarias complejas; 2) fisuras en las placas coronarias; 3) trombos recientes; e 4) inflamación de la placa. La conversión de una lesión estable y asintomática en una placa rota e inestable envuelve muchos procesos. Los autores se proponen revisar de manera crítica la literatura reciente sobre los mecanismos envueltos en la génesis de la placa coronaria aterosclerótica vulnerable, bien como los mecanismos fisiopatológicos de la ruptura; será discutido el concepto de paciente vulnerable, y serán comentados los métodos diagnósticos (consagrados y experimentales) y las perspectivas de tratamiento de esta patología...(AU)

Limitaciones de la creatinina como marcador de filtración en la nefrotoxicidad inducida por contrastes en pacientes sometidos a cateterismo cardíaco / Limitations of creatinine as a filtration marker in contrast-induced neprhotoxicity in patients undergoing cardiac catheterization

Introducción:El objetivo del estudio fue determinar si el cálculo de la tasa de filtración glomerular (TFG) por la fórmula de Cockroft-Gault proporciona una mejor estimación de la función renal (FR) que la creatinina sérica (CrS) para detectar nefrotoxicidad (NTIC) en pacientes (PS) expuestos a medios de contraste (MC). Métodos: 133 PS con CrS basal hasta 1.2 mg/dL sometidos a cateterismo cardíaco (CC) fueron incluidos, y colectadas muestras de sangre antes y 48 h después del procedimiento. Resultados: En condiciones basales los PS fueron divididos en: Grupo I (TFG<60 mL/min, n=15) y Grupo II (TFG≥60 mL/min, n=118); el Grupo I presentaba CrS más alta (1.01 ± 0.14 vs 0.88 ± 0.18 mg/dL; P=0.007), TFG baja (49.1 ± 6.7 vs 101.1 ± 29.9 mL/min; P<0.0001) y se caracterizaban por ser: personas mayores de edad (P=0.006), predominio en mujeres, menor peso (P<0.0001) y menor estatura. Después del cateterismo la incidencia de nefrotoxicidad fue 20.3%. Los PS fueron divididos en 2 nuevos grupos: con nefrotoxicidad (CPFR, n=27) y sin nefrotoxicidad (SPFR, n=106); en el grupo CPFR la CrS aumentó de 0.80 ± 0.20 para 1.10 ± 0.23 mg/dL (P=0.0001) y la TFG disminuyó de 98.1 ± 46.0 para 69.8 ± 31.0 mL/min (P=0.0001). Conclusiones: La TFG calculada con la fórmula de Cockcroft-Gault fue más eficaz y rápida que la CrS para evaluar la función renal antes y después de la exposición a MC, y permitió identificar pacientes que aun con niveles normales de CrS ya presentan algún grado de disfunción renal (prevalencia de 11.3%

Cardiomiopatia Hipertrófica Obstrutiva Médio-Ventricular / Mid-Ventricular Hypertrophic Obstructive Cardiomyopathy

A cardiomiopatia hipertrófica obstrutiva médio-ventricular é uma variante rara (1%) da cardiomiopatia hipertrófica obstrutiva. Neste relato de caso, apresentamos uma paciente encaminhada para realização de cateterismo cardíaco eletivo por angina e dispneia aos moderados esforços, sem obstrução coronariana significativa e com ventriculografia esquerda, demostrando cardiomiopatia hipertrófica obstrutiva médio-ventricular com um gradiente pressórico intraventricular de 130 mmHg...

Mid-ventricular hypertrophic obstructive cardiomyopathy is a rare variant form (1%) of hypertrophic obstructive cardiomyopathy. In this case, we report a patient referred for elective cardiac catheterization due to angina and dyspnea on moderate exertion, with no significant coronary obstruction, and left ventriculography indicating the presence of mid-ventricular hypertrophic obstructive cardiomyopathy with an intraventricular pressure gradient of 130 mmHg...

Efeitos do exercício físico no estado inflamatório crônico de baixo grau induzido pela obesidade / Effects of exercise in chronic inflammatory state of low level induced by obesity

A obesidade hoje é caracterizada como um estado inflamatório crônico de baixo grau, devido ao aumento sistêmico de adipocinas liberadas pelo tecido adiposo branco, que atualmente é conhecido como um importante órgão endócrino. Há um consenso que o exercício físico promove benefícios no que diz respeito ao controle do peso corporal bem como na proteção contra doenças crônicas, como as doenças cardiovasculares, diabetes mellitus tipo 2 e Obesidade. Os efeitos anti-inflamatórios decorrentes da pratica regular de exercícios físicos, foram propostos por vários autores. Isto serviu para dar sustentação ao objetivo deste estudo que consistiu em identificar o efeito do exercício físico, como ferramenta de prevenção e combate ao processo inflamatório provocado por um aumento da circulação sistêmica de adipocinas. As considerações finais demonstraram que o exercício físico regular provocou alterações do perfil de adipocinas, reduzindo a secreção da Leptina, TNF-α e aumentando as concentrações de adiponectina, resultando em um efeito protetor das doenças associadas à inflamação crônica de baixo grau

The Obesity is now characterized as a chronic lowgrade inflammatory state due to the systemic increase of adipokines released by white adipose tissue, which is currently known as an important endocrine organ. There is a consensus that physical exercise promotes benefits with regard to the control of body weight and protect against chronic diseases such as cardiovascular diseases, type 2 diabetes mellitus and obesity.The anti-inflammatory due to the regular practice of physical activity, effects have been proposed by various authors. This served to support the objective of this study was to identify the effect of physical exercise, and the prevention and combating inflammatory process caused by an increase in systemic circulation of adipokines tool. The final considerations have shown that regular exercise induces alterations in adipokine profile, reducing the secretion of leptin, TNF-α and increasing concentrations of adiponectin, resulting in a protective effect against diseases associated with chronic lowgrade inflammation

Associação entre remodelamento vascular e núcleo necrótico em artérias coronárias: análise por ultrassom intracoronário com Histologia Virtual® / Association between vascular remodeling and necrotic core in coronary arteries: Virtual Histology intravascular ultrasound analysis

INTRODUÇÃO: Estudos anatomopatológicos sugerem a associação de remodelamento vascular positivo e placas coronárias vulneráveis. O objetivo deste estudo foi avaliar se existe correlação entre o grau de remodelamento vascular positivo e o porcentual de núcleo necrótico em lesões ateroscleróticas coronárias. MÉTODOS: Foram estudados 270 cortes transversais obtidos pela Histologia Virtual® de 30 pacientes, os quais apresentavam remodelamento positivo em segmento de artéria coronária com lesão > 50%, identificada pela angiografia coronária. Foram avaliados 7 cortes transversais por segmento de artéria coronária, incluindo o corte transversal com o maior índice de remodelamento arterial, denominado corte transversal de interesse (corte transversal 4). RESULTADOS: A média de idade foi de 60,8 ± 8,8 anos, 80% eram do sexo masculino e 30% diabéticos. Angina instável foi a apresentação clínica mais frequente (56,6%) e a artéria descendente anterior foi o vaso mais analisado (43%). A área de referência do vaso foi de 15,5 ± 4,9 mm² e o índice de remodelamento no corte transversal 4 foi de 1,2 ± 0,1. Análise de variância de medidas repetidas mostrou maior porcentual de núcleo necrótico no corte transversal de interesse (P < 0,001). Observamos correlação positiva do remodelamento arterial coronário com o núcleo necrótico (r = 0,79; P < 0,001). CONCLUSÕES: O remodelamento positivo da artéria coronária está associado à presença de núcleo necrótico, o qual caracteriza placas ateromatosas vulneráveis. A pesquisa de remodelamento arterial positivo pode ser estratégia útil para a detecção de placas vulneráveis antes de sua ruptura.

BACKGROUND: Anatomopathological studies suggest an association of positive vascular remodeling and vulnerable coronary plaques. The objective of this study was to verify whether there is a correlation between positive vascular remodeling and necrotic core in atherosclerotic coronary lesions. METHODS: We studied 270 cross sections obtained by Virtual Histology® in 30 patients who had positive remodeling in coronary artery segments with lesions > 50%, identified by coronary angiography. Seven cross sections were assessed per segment of coronary artery, including the cross section with the highest remodeling index, denominated cross section of interest (cross section 4). RESULTS: Mean age was 60.8 ± 8.8 years, 80% were male and 30% were diabetic. Unstable angina was the most frequent clinical presentation (56.6%) and the left anterior descending artery was the most analyzed vessel (43%). The vessel reference area was 15.5 ± 4.9 mm² and the remodeling index in cross section 4 was 1.2 ± 0.1. Repeated measures analysis of variance showed a higher percentage of necrotic core in the cross section of interest (P < 0.001). We observed a positive correlation of coronary artery remodeling and necrotic core (r = 0.79; P < 0.001). CONCLUSIONS: Positive coronary artery remodeling is associated to the presence of necrotic core, which characterizes vulnerable atherosclerotic plaques. The search for positive arterial remodeling may be a useful strategy for detecting vulnerable plaques before rupture.

Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis.

OBJECTIVES: To test the local delivery of sirolimus nanoparticles following percutaneous transluminal coronary angioplasty (PTCA) to treat in-stent restenosis (ISR) in a swine model. BACKGROUND: Coronary bare-metal stent (BMS) implantation reduces major adverse cardiac events when compared with PTCA; however, ISR rates remain high. METHODS: Eighteen swine underwent BMS deployment guided by intravascular ultrasound (IVUS). Of these, 16 developed ISR (1 stent/swine) and underwent angioplasty with a noncompliant balloon (PTCA-NC). The animals were then randomized into four groups for local infusion of sirolimus nanoparticles through a porous balloon catheter, as follows: (1) PTCA-NC alone (control); (2) PTCA-NC + (polylactic acid)-based nanoparticle formulation (anionic 1); (3) PTCA-NC + (polylactic-co-glycolic acid)-based nanoparticle formulation (anionic 2); and (4) PTCA-NC + Eudragit RS nanoparticle formulation (cationic). Coronary angiography and IVUS follow-up were performed 28 days after ISR treatment. RESULTS: There was one episode of acute coronary occlusion with the cationic formulation. Late area loss was similar in all groups at 28 days according to IVUS. However, luminal volume loss (control = 20.7%, anionic 1 = 4.0%, anionic 2 = 6.7%, cationic = 9.6%; P = 0.01) and neointimal volume gain (control = 68.7%, anionic 1 = 17.4%, anionic 2 = 29.5%, cationic = 31.2%; P = 0.019) were significantly reduced in all treatment groups, especially in anionic 1. CONCLUSIONS: PTCA-NC followed by local infusion of sirolimus nanoparticles was safe and efficacious to reduce neointima in this model, and this strategy may be a promising treatment for BMS ISR. Further studies are required to validate this method in humans.

Friable but treatable: coronary artery dissections in Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare connective tissue disorder associated with arterial dissection or rupture. Percutaneous coronary intervention (PCI) is often critical in patients with this syndrome because their coronary arteries are prone to dissection, enhancing the risk of stent borders dissection when conventional stent deployment pressures are used. Coronary artery bypass graft (CABG) treatment for these patients may also raise concerns because the left internal mammary artery is probably friable. Therefore, coronary artery revascularization in vascular Ehlers-Danlos syndrome either using PCI or CABG is challenging due to the arteries friability. A small number of cases have been published describing the friability of the vessels and associated complications; nevertheless, the optimum treatment remains unclear. We report the case of a 54-year-old woman treated successfully with PCI and CABG in two different acute coronary syndrome episodes, in which specific technical issues related to both procedures were decisive.

Identificação de genes envolvidos na síntese de proteínas de células musculares lisas com expressão aumentada em placas ateromatosas associados a hiperplasia neointimal após implante de stents não-farmacológicos: estudo GENESIS-R / Identification of genes involved in smooth muscle cell protein synthesis with increased expression in atheromathous plaques associated to neointim al hyperplasia after bare-metal stenting: GENESISI-R Study

Introdução: A reestenose coronária é um fenômeno pouco compreendidoe que permanece como um desafio mesmo na era dos stents farmacológicos. Este estudo tem como objetivo identificar genes envolvidos na síntese de proteínas estruturais e funcionais de células musculares lisas com expressão aumentada em placas ateromatosas de humanos associadosa hiperplasia neointimal após o implante de stents não-farmacológicos. Métodos: Placas ateromatosas foram obtidasmediante aterectomia direcionada, previamente ao implante do stent. A análise da expressão dos genes foi realizada utilizando-se o sistema Affymetrix GeneChip. Os pacientes foramsubmetidos a ultrassom intracoronário 6 meses após o procedimento para análise volumétrica intrastent. Foi avaliada a correlação entre a expressão gênica de placas ateromatosas e o porcentual de hiperplasia intimal intrastent. Resultados: A maioria dos pacientes era do sexo masculino (85,7%), com60,2 ± 11,4 anos de idade, 35,7% eram diabéticos e o porcentual de hiperplasia intimal intrastent foi de 29,9 ± 18,7%.Não houve variação do porcentual de hiperplasia intimal intrastent entre os pacientes com ou sem diabetes (29,5% vs. 30,7%; P = 0,89). Não houve correlação entre a extensão do stent e o porcentual de hiperplasia intimal intrastent (r = -0,26; P = 0,26) ou entre o diâmetro do stent e o porcentual dehiperplasia intimal intrastent (r = 0,14; P = 0,56). Oito genes envolvidos na síntese de proteínas estruturais e funcionais de células musculares lisas apresentaram correlação positiva como porcentual de hiperplasia intimal intrastent. Conclusões: As lesões coronárias de novo apresentam expressão aumentada de genes relacionados com a síntese de proteínas estruturais e funcionais de células musculares lisas associados a futurahiperplasia neointimal intrastent significativa, surgindo como novos alvos terapêuticos.

First-in-man study of simvastatin-eluting stent in de novo coronary lesions: the SIMVASTENT study.

BACKGROUND: Statins have anti-inflammatory and antiproliferative properties irrespective of their cholesterol-lowering effects. The aim of the present study was to evaluate a simvastatin-eluting stent (SimvES) in the treatment of de novo coronary lesions. METHODS AND RESULTS: Forty-two patients with de novo coronary artery lesions were assigned to SimvES, bare-metal stent (BMS) or everolimus-eluting stent (EES) implantation followed by intravascular ultrasound (IVUS) for neointimal quantitative analysis. Six months later, quantitative coronary angiography (QCA) and IVUS were repeated. QCA showed no binary restenosis, a mean in-stent late loss of 1.05 ± 0.25 mm (BMS, 1.12 ± 0.48 mm; EES, 0.20 ± 0.16 mm) and a diameter stenosis of 33.5 ± 7.1% (BMS, 35.5 ± 15.30%; EES, 7.2 ± 3.12%). Control IVUS showed a mean in-stent obstruction of 18.3 ± 9.4% (BMS, 32.8 ± 19.1%; EES, 9.8 ± 2.4%) and a neointimal volume index of 1.58 ± 0.75 mm(3)/mm (BMS, 2.93 ± 1.76 mm(3)/mm; EES, 0.80 ± 0.16 mm(3)/mm). Thrombus, late incomplete apposition and major adverse cardiac events were not observed. CONCLUSIONS: In this sample of patients with de novo coronary lesions, the use of a SimvES was not related to major adverse cardiac events, but it was associated with a higher level of neointimal proliferation than expected.

Endovascular repair of ascending aorta and coronary stent implantation.

Endovascular treatment of ascending aorta pseudoaneurysms with coronary stents implantation at the same procedure was feasible, although longer followup is necessary.

Perfil da intervenção coronária percutânea no infarto agudo do miocárdio com supradesnivelamento do segmento ST no Brasil de 2006 a 2010: Registro CENIC / National profile of percutaneous coronary intervention in acute ST elevation myocardial infarction in Brazil from 2006 to 2010: the CENIC Registry

Introdução: O infarto agudo do miocárdio (IAM) persiste comoimportante causa de morbidade e mortalidade. Este estudo visa a delinear o panorama nacional da intervenção coronária percutânea (ICP) no cenário do IAM, analisando diferentes períodos e regiões do Brasil, com enfoque na ICP primária e nos tratamentos adjuntos farmacológicos e mecânicos.Métodos: Foram analisados dados de 20.004 pacientes com diagnóstico de IAM com supradesnivelamento dosegmento ST (IAMCSST) e submetidos a ICP, provenientes do Registro CENIC (Central Nacional de Intervenções Cardiovasculares), de janeiro de 2006 a dezembro de 2010. Esses dados são oriundos de 252 centros localizados em22 Estados das cinco regiões do País. Resultados: A ICP primária correspondeu a 57,8% das ICPs realizadas no contexto do IAM, seguida de ICP eletiva pós-IAMCSST (35,7%), ICP de resgate (6,1%) e ICP facilitada (0,4%). A evolução ao longo dos anos evidencia aumento progressivo do número de ICPs primárias no Brasil, partindo de 56,7% do total em 2006 para 71,6% em 2010. O tempo médio porta-balão da ICP primária no Brasil nesse período foi de 2 horas. A aspiração de trombos aumentou de 0,4%em 2006 para 8,2% dos casos em 2010. A taxa média de sucesso do procedimento foi de 93,8%, enquanto a de óbito hospitalar foi de apenas 2,8%. Conclusões: A ICP no cenário do IAMCSST vem apresentando avanços de 2006 a 2010, embora de maneira heterogênea nas diferentes regiões doBrasil, mediante aumento das taxas de ICP primária e maior utilização de dispositivos de aspiração de trombo, osquais ainda não foram incorporados na rotina. Investimentos em recursos humanos e implementação de protocolos de atendimento constituem elementos essenciais para a otimização do tempo porta-balão e para a melhora dos resultados clínicos.

Background: Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality. This study aims to outline the national profile of percutaneous coronary intervention(PCI) in the setting of AMI, analyzing different time periods and geographic regions, with focus on primary PCI and adjunctive pharmacological and mechanical treatments. Methods: Data from 20,004 patients with ST elevationmyocardial infarction (STEMI) undergoing PCI and included in the CENIC Registry (National Center of Cardiovascular Interventions) from January 2006 to December 2010 wereincluded in this study. Data were obtained from 252 centers located in 22 states from five different geographic regions in the country. Results: Primary PCI accounted for 57.8% of PCI performed in the setting of AMI, followed by elective PCI after STEMI (35.7%), rescue PCI (6.1%) and facilitated PCI (0.4%). The evolution over time showed a progressiveincrease in the number of primary PCIs in Brazil, from 56.7% in 2006 to 71.6% in 2010. The mean door-to-balloon timeof primary PCI in Brazil during this period was 2 hours. Thrombus aspiration increased from 0.4% in 2006 to 8.2%of cases in 2010. Procedural success rate was 93.8%, while in-hospital mortality was only 2.8%. Conclusions: PCI in the setting of STEMI has improved from 2006 to 2010, althoughheterogeneously in the different regions of Brazil, due to increased primary PCI rates and higher use of thrombusaspiration devices, which have not been incorporated in the routine practice. Investments in staff training and implementation of clinical protocols are essential to optimize the door-to-balloon time and improve clinical outcomes.

Endovascular approach to treat ascending aortic pseudoaneurysm in a patient with previous CABG and very high surgical risk.

Pseudoaneurysm of the ascending aorta is an uncommon pathology and a challenge in high-risk patients who undergo conventional surgery because of high operative morbidity and mortality. Endovascular exclusion of an aortic pseudoaneurysm using an endoprosthesis is a less invasive approach, but few such cases have been reported. Moreover, the use of this approach poses unique therapeutic challenges because there is no specific endoprosthesis for ascending aortic repair, particularly to treat patients with previous coronary artery bypass graft (CABG). We describe the case of a 74-year-old patient who had undergone CABG and later presented with an iatrogenic ascending aortic pseudoaneurysm that occurred during an angiography. This patient was at very high risk for surgical treatment and, therefore, an endovascular approach was adopted: percutaneous coronary intervention for the left main coronary artery, left anterior descending and left circumflex native coronary arteries followed by endovascular endoprosthesis deployment in the ascending aorta to exclude the pseudoaneurysm. Both procedures were successfully performed, and the patient was discharged without complications 4 days later. At 5 months' clinical follow-up, his clinical condition was good and he had no complications.

Erectile dysfunction and coronary artery disease: an association of higher risk in younger men.

INTRODUCTION: The association between erectile dysfunction (ED) and coronary artery disease (CAD) has been described in various settings, but it is unclear if there is an independent interaction with age. AIM: To investigate the interaction of age in the association between ED and CAD. METHODS: This case-control study was conducted among 242 patients referred for elective coronary angiography. One hundred fourteen patients with significant CAD were identified as cases and 128 controls without significant CAD. ED was evaluated by the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire, determined by a score ≤ 25 points. MAIN OUTCOME MEASURES: Significant CAD was based on stenosis of 50% or greater in the diameter in at least one of the major epicardial vessels or their branches. The analysis was conducted in the whole sample and according to the age strata, controlling for the effects of cardiovascular risk factors, testosterone, and C-reactive protein. Results. Patients had on average 58.3 ± 8.9 years. CAD and ED were associated exclusively in patients younger than 60 years (ED in 68.8% of patients with CAD vs. 46.7% of patients without CAD, P = 0.009). The association was independent of cardiovascular risk factors, testosterone and C-reactive protein (risk ratio 2.3, 95% confidence interval from 1.04 to 5.19). Severity of CAD was higher in patients younger than 60 years with ED. CONCLUSIONS: Men with less than 60 years of age who report ED presented a higher risk of having chronic CAD and more severe disease diagnosed by coronary angiography.

Modelo experimental de reestenose intrastent em artérias coronárias de suínos: efeito do implante de stent sobredimensionado / Experimental model of in-stent restenosis in swine coronary arteries: effect of oversized stent deployment

INTRODUÇÃO: Há múltiplos modelos experimentais em animais, entretanto o modelo suíno é o que apresenta características anatômicas e funcionais mais próximas às humanas. Assim sendo, esse trabalho foi realizado com o objetivo de desenvolverr e implementar um protocolo experimental de indução de hiperproliferação neointimal em suínos, visando à criação de técnicasw de lesão vascular simulando a reestenose. Método: De agosto de 2006 a março de 2009, 69 suínos jovens da raça Large White foram submetidos a cinecoronariografia seguida de lesão vascular com implante de 102 stents sobredimensionados, guiados por ultrassom intracoronário. Em 28 dias foi realizado reestudo com nova cinecoronariografia e ultrassom intracoronário. Resultados: O diâmetro luminal mínimo e a área luminal mínima imediatamente após o implante de stent no grupo stent sobredimensionado foram maiores em comparação ao grupo controle...

BACKGROUND: There are several experimental animal models, but, the swine model is the most similar to human anatomic and physiologic characteristics. Therefore, this study was carried out to develop and implement an experimental protocol of vascular neointimal hyperplasia induction in swine, aiming at creating vascular injury techniques simulating restenosis. METHOD: From August 2006 to March 2009, 69 young Large White swine underwent coronary angiography followed by vascular injury and implantation of 102 oversized stents guided by intravascular ultrasound. After 28 days a new coronary angiography and intravascular ultrasound was performed. RESULTS: The minimal luminal diameter and the minimal luminal area immediately after the stent deployment in the group treated with an oversized stent were significantly higher when compared to the control group (3.5 ± 0.3 mm vs. 3 ± 0.2 mm, P < 0.0001 and 40.7 ± 0.3 mm² vs. 30.2 ± 0.2 mm², P < 0.0001). The binary restenosis rate in the group treated with an oversized stent was 92% (69/75 stents), whereas it was 12% (3/25 stents) in the control group, with a statistically significant difference (P < 0.0001). The neointimal hyperplasia volume was significantly higher in the group treated with an oversized stent in comparison to the control group (5.9 ± 0.8 mm³/stent mm vs. 1.8 ± 0.7 mm³/stent mm, P < 0.0001). CONCLUSION: The proposed experimental model of neointimal proliferation induction in swine is effective in inducing instent hyperplasia, and therefore it may be used for the study of the pathophysiologic mechanisms of in-stent restenosis as well as for therapeutic purposes, such as the evaluations of new drugs, new devices and new drug-eluting stents for the prevention and treatment of in-stent restenosis.

The importance of the interaction between leukocyte integrin Mac-1 and platelet glycoprotein Ib-a for leukocyte recruitment by platelets and for the inflammatory response to vascular injury.

OBJECTIVE: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury. METHODS: A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses. RESULTS: The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9+/-5.0% of the cell total versus anti-M2: 2.0+/-1.6%, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3+/-12.9% versus anti-M2: 24.6+/-10.8%, p=0.047 and control: 7.9+/-3.0% versus anti-M2: 3.3+/-1.3%, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0+/-2.9% of the cell total versus anti-M2: 1.8+/-0.5%; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8+/-1.7% versus anti-M2: 2.0+/-1.2%; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395+/-3,549 microm(2) versus anti-M2: 4,561+/-4,915 microm(2); p=0.012). CONCLUSION: Leukocyte recruitment after a vascular injury depends on the Mac-1-GPIba interaction and the neutralization of this interaction inhibits cell proliferation and neointimal formation.

The importance of the interaction between leukocyte integrin Mac-1 and platelet glycoprotein Ib-a for leukocyte recruitment by platelets and for the inflammatory response to vascular injury / Importância da interação entre a integrina Mac-1 dos leucócitos e a glicoproteína Iba das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular

OBJETIVO: Avaliar a importância da interação entre a integrina Mac-1 dos leucócitos (a Mb 2) e a glicoproteína (GP) Iba das plaquetas para o recrutamento de leucócitos após a lesão vascular e o efeito da neutralização da interação Mac-1-GPIba sobre a proliferação celular e a hiperplasia neointimal desencadeadas por lesão vascular. MÉTODOS: Um peptídeo denominado M2 ou anticorpo anti-M2 foi desenvolvido para bloquear a interação Mac-1-GPIba . Esse peptídeo foi injetado e comparado com anticorpo-controle em camundongos C57B1/6J submetidos a lesão vascular da artéria femoral com corda-guia. Um, cinco ou 28 dias após a lesão vascular, as artérias femorais foram retiradas para a realização de morfometria e imuno-histoquímica. RESULTADOS: O bloqueio da interação Mac-1-GPIba promoveu uma redução estatisticamente significativa do número de leucócitos na camada média no primeiro dia após a lesão vascular (controle: 7,9±5,0 por cento do total de células versus anti-M2: 2,0±1,6 por cento, p=0,021), bem como determinou uma diminuição estatisticamente significativa do acúmulo de leucócitos na neoíntima em cinco e 28 dias (controle: 42,3±12,9 por cento versus anti-M2: 24,6±10,8 por cento, p=0,047 e controle: 7,9±3,0 por cento versus anti-M2: 3,3±1,3 por cento, p=0,012; respectivamente). A proliferação celular na camada média do vaso em cinco dias pós-lesão foi reduzida com o bloqueio da interação Mac-1-GPIba (controle: 5,0±2,9 por cento do total de células versus anti-M2: 1,8±0,5 por cento; p=0,043), assim como houve diminuição significativa da proliferação celular na camada íntima do vaso em 28 dias (controle: 3,8±1,7 por cento versus anti-M2: 2,0±1,2 por cento; p=0,047). O bloqueio da interação Mac-1-GPIba também determinou uma redução estatisticamente significativa do espessamento intimal em 28 dias pós-lesão (controle: 10.395±3.549 µm² versus anti-M2: 4.561±4.915 ...

OBJECTIVE: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury. METHODS: A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses. RESULTS: The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9±5.0 percent of the cell total versus anti-M2: 2.0±1.6 percent, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3±12.9 percent versus anti-M2: 24.6±10.8 percent, p=0.047 and control: 7.9±3.0 percent versus anti-M2: 3.3±1.3 percent, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0±2.9 percent of the cell total versus anti-M2: 1.8±0.5 percent; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8±1.7 percent versus anti-M2: 2.0±1.2 percent; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395±3,549 µm² versus anti-M2: 4,561±4,915 µm²; ...

Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events.

BACKGROUND: Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. METHODS AND RESULTS: We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 microg/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. CONCLUSIONS: The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.

Importância da interação entre a integrina Mac-1 leucócitos e a glicoproteína Ib alfa das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular / The importance of the leukocyte integrin Mac-1 and platelet glycoprotein Ib? interaction for the leukocyte recruitment by platelets and for the inflammatory response to vascular injury

INTRODUÇÃO: A interação entre leucócitos e plaquetas é fundamental para o início e a progressão da reestenose e da aterosclerose. Recentemente foi evidenciado em estudos in vitro que a integrina Mac-1 dos leucócitos se liga à glicoproteína Ibalfa (GP Ibalfa) das plaquetas e que esta interação possui uma função central na firme adesão e transmigração de leucócitos em locais de deposição de plaquetas. Entretanto, não há estudos in vivo que avaliam a importância da interação entre a integrina Mac-1 dos leucócitos e a GP Ibalfa das plaquetas (alfaMbeta2-GP Ibalfa) em modelo experimental de lesão vascular. MÉTODO: Um peptídeo denominado M2 ou anticorpo anti-M2 foi desenvolvido para bloquear a interação da integrina Mac-1 dos leucócitos com a GP Ibalfa das plaquetas, visando, deste modo, inibir a adesão de leucócitos na superfície do vaso coberta por plaquetas, a proliferação celular e a hiperplasia neointimal. Este peptídeo foi injetado e comparado com anticorpo-controle em camundongos C57B1/6J submetidos à lesão vascular da artéria femoral com corda-guia. Um dia (controle: n= 6; anti-M2: n= 6), 5 dias (controle: n= 9; anti-M2: n= 9) ou 28 dias (controle: n= 9; anti-M2: n= 9) após a lesão vascular, as artérias femorais foram retiradas para a realização de morfometria e imunohistoquímica. RESULTADOS: O bloqueio da interação alfaMbeta2-GP Ibalfa promoveu redução estatisticamente significativa de 75% do número de leucócitos na camada média no primeiro dia após a lesão vascular...

INTRODUCTION: The interaction between leukocytes and platelets is fundamental for the beginning and the progression of restenosis and atherosclerosis. Recent in vitro studies have shown that the leukocyte integrin Mac-1 binds to the platelet glycoprotein (GP) Ibalfa, and this interaction plays a central role in the leukocyte firm adhesion and transmigration at sites of platelet deposition. However, there is no in vivo study evaluating the importance of the integrin Mac-1 and GP Ibalfa (alfaMbeta2-GP Ibalfa) interaction in experimental models of vascular injury. METHODS: A peptide termed M2 or anti-M2 antibody was developed to block the leukocyte Mac-1 and platelet GP Ibalfa interaction, aiming to inhibit the adhesion of leukocytes to the platelet-coated surface of vessels as well as the cellular proliferation and the neointimal hyperplasia. The peptide was injected and compared with a control-antibody in C57B1/6J mice subjected to wire-induced femoral artery injury. One day (control: n= 6; anti-M2: n= 6), 5 days (control: n= 9; anti-M2: n= 9) or 28 days (control: n= 9; anti-M2: n= 9) after vascular injury, the femoral arteries were harvested for morphometry and immunohistochemistry. RESULTS: The alfaMbeta2-GP Ibalfa interaction blockade promoted a statistically significant 75% reduction in leukocytes in the medial layer on the first day after vascular injury (control: 7.9 ± 5.0% out of the total cells in the medial layer versus anti-M2: 2.0 ± 1.6%; p=0.021), as well as determined a statistically significant 42% decrease 5 days later (control: 42.3 ± 12.9% out of the total cells in the neointima versus anti-M2: 24.6 ± 10.8%; p=0.047), and a 58% decrease in leukocyte accumulation in the developing neointima 28 days later (control: 7.9 ± 3.0% versus anti-M2: 3.3 ± 1.3%; p=0.012). The cellular proliferation in the vessel medial layer 5 days after vascular injury presented a statistically significant 64% reduction by the alfaMbeta2-GP Ibalfa interaction blockade...

Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury.

BACKGROUND: Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise alphaMbeta2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified. METHODS AND RESULTS: Our previous studies have established the P201-K217 sequence in the alphaMI domain as the binding site for platelet glycoprotein (GP) Ibalpha. Here we report that antibody targeting of alphaM(P201-K217) reduced alphaMbeta2-dependent adhesion to GP Ibalpha but not other alphaMbeta2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-alphaM(P201-K217) inhibited the firm adhesion of both human and murine leukocytes to adherent platelets under laminar flow conditions. In a mouse femoral artery wire injury model, antibody targeting of alphaM(P201-K217) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening. CONCLUSIONS: This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.